published_or_final_version / Pathology / Master / Master of Medical Sciences

Thesis (D.PT.)--Sage Colleges, 2010. / "May 2010." "A Capstone project for PTY 768 presented to the faculty of The Department of Physical Therapy Sage Graduate School in partial fulfillment of the requirements for the degree of Doctor of Physical Therapy." Includes bibliographical references.

Introduction: The idiopathic inflammatory myopathies (IIM): dermatomyositis (DM) and polymyositis (PM) have been historically defined by broad clinical and pathological criteria. These conditions affect both adults and children with clinical features including muscle weakness, skin disease and internal organ involvement. Using a clinico-serological approach DM and PM can be defined into more homogeneous subsets. Myositis-specific autoantibodies (MSAs) are directed against cytoplasmic or nuclear components involved in key regulatory intra-cellular processes including protein synthesis, translocation and gene transcription. Over the last few years MSAs have been better characterised including autoantibodies directed against the aminoacyl tRNA-synthetase (ARS) enzymes, the signal recognition particle and the Mi-2 protein. Aim: The overall aim of this thesis is to describe a comprehensive clinical and serological study of adult and juvenile IIM. Autoantigen targets including novel specificities were identified using protein immunoprecipitation. Results: The first part of this thesis is a descriptive study on known myositis autoantibodies in adult IIM, confirming the significant association of interstitial pneumonia with anti-ARS, severe myopathy with anti-SRP, and classic DM with anti-Mi-2 serotype. In the next section, new autoantigen systems in adult IIM are described including a new anti-ARS (anti-Zo) in the anti-synthetase syndrome. Further autoantibodies directed against small ubiquitin-like modifier enzyme and a p155/140 autoantigen are major serological subsets in adult DM, the latter significantly associated with malignancy. The final section outlines a large serological study of juvenile DM (JDM) and JDM-overlap showing the frequency and clinical associations of MSAs and myositis-associated autoantibodies, including work on two new major subsets anti-p155/140 and anti-p140, which appear to define more severe disease. Conclusion: The work in this thesis highlights the importance of autoimmunity in IIM and suggests a new approach where MSAs can classify patients into clinical syndromes, which predict outcomes and may as a result influence treatment strategies.

Yes / To assess whether magnetic resonance imaging (MRI)-based measurements of T2, fat fraction, diffusion tensor imaging, and muscle volume can detect differences between the muscles of myositis patients and healthy controls, and to identify how they compare with semi-quantitative MRI diagnosis. Sixteen myositis patients and 16 age- and gender-matched healthy controls underwent MRI of their thigh. Quantitative MRI measurements and radiologists' semi-quantitative scores were assessed. Strength was assessed using an isokinetic dynamometer. Fat fraction and T2 values were higher in myositis patients whereas muscle volume was lower compared to healthy controls. There was no difference in diffusion. Muscle strength was lower in myositis patients compared to healthy controls. In a subgroup of eight patients, scored as unaffected by radiologists, T2 values were still significantly higher in myositis patients. Quantitative MRI measurements can detect differences between myositis patients and healthy controls. Changes in the muscles of myositis patients, undetected by visual, semi-quantitative scoring, can be detected using quantitative T2 measurements. This suggests that MRI T2 values may be useful for the management of myositis patients. / National Institute for Health Research (NIHR) Leeds (BRC) and Health Education England

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 4 uppsatser.

No description available.

Background: The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases comprising of polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). They are characterised primarily by muscle weakness, and can present with extramuscular manifestations such as skin rashes, interstitial lung disease and malignancy. Aims: This aim of this study was to identify novel genetic risk factors in IIM and to further elucidate the relationship between genotype and serotype. Methods: 2,566 IIM samples were collected from 14 countries through the Myositis Genetics Consortium (MYOGEN) and genotyped on the Immunochip, a custom array covering 186 established autoimmune susceptibility loci. SNP2HLA was used to impute classical HLA alleles and constituent amino acids. Results: In a combined IIM analysis, the HLA region and PTPN22 reached genome-wide significance (p<5x10-8). A further nine regions reached suggestive significance (p<2.25x10-5) including UBE2L3, STAT4 and CD28 that have been implicated in autoimmune disease previously. Independent effects were seen within the STAT4 region. In a PM subgroup analysis (n=931), the HLA region and PTPN22 reached genome-wide significance. A further seven regions reached suggestive significance including SLC26A1/IDUA and RGS1. In an adult and juvenile DM analysis (n=1,360), only the HLA region reached genome wide significance. Three loci reached suggestive significance including GSDMB. In the IBM analysis (n=252), only the HLA region reached genome wide significance and 3 loci reached suggestive significance, including the CCR2 locus. Identification of exonic and eQTL SNPs has localised association signals to several potential causal variants. HLA imputation on the combined dataset confirmed that alleles of the 8.1 ancestral haplotype (AH) are most strongly associated with IIM. The cohort was stratified in to clinical subgroups. In PM the strongest effect was found with HLA-DRB1*03:01 with an independent effect with HLA-B*08:01. Amino acid position 74 lies within the peptide binding groove and may explain the risk in HLA-DRB1. HLA-B*08:01 was the most associated variant in both DM and JDM, with independent effects of amino acid position 57 of HLA-DQB1 in DM and HLA-C*02:02 in JDM. In IBM, the strongest associations were with amino acids positions 26 and 11 of HLA-DRB1.HLA imputation was conducted on antibody subgroups. The most associated variant for anti-Jo-1 and anti-PM/Scl antibodies was with amino acid 74 of HLA-DRB1. Alleles of the 8.1 AH were most associated with anti-TIF1-γ, anti-SAE and anti-cN1A antibodies. Alleles independent of the 8.1 AH were replicated such as anti-Mi-2 antibodies and HLA-DRB1*07:01, and anti-HMGCR antibodies and HLA-DRB1*11. Conclusions: This represents the largest study to date in IIM and has considerably expanded our knowledge about the genetic architecture of this rare disease. This study has identified novel disease susceptibility genes for IIM and independent associations with PM and DM, IBM and antibody subgroups that show that stratifying patients in to more homogenous cohorts is important to expand our knowledge of IIM. Ongoing sample collection is required to identify additional genes and environmental risk factors that lead to the development of IIM, and to expand our limited understanding of the pathogenesis of this disease.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20273号 / 医博第4232号 / 新制||医||1021(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 山田 亮, 教授 清水 章 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Sporadic Inclusion Body Myositis (sIBM) is an inflammatory muscle disease that strikes individuals at random and accounts for approximately 1/3 of all idiopathic inflammatory myopathies. It is characterized by progressive weakness of distal and proximal muscles and is the most common muscle disorder in individuals over 50 years of age. Currently, there is no known cause, cure, or enduring treatment for sIBM, although a number of theories as to its cause have been proposed. One theory proposes that activation of the inflammatory/ immune response is the primary trigger resulting in muscle degeneration and protein abnormalities, while an alternative theory suggests that sIBM is a degenerative muscle disease with abnormal pathogenic protein accumulation, in particular Abeta, being a primary cause that triggers an inflammatory/ immune response. Mitochondrial abnormalities have been observed in skeletal muscle from patients diagnosed with the disease, however the role of the mitochondria in disease pathology is still unclear. The aim of this dissertation was to evaluate: 1) the role of the mitochondria in the development of sIBM and 2) the role of amyloid beta on mitochondrial function in skeletal muscle. A better understanding of the role of the mitochondria in the development of sIBM may help to identify novel prevention and/ or treatment strategies. / Ph. D.